Tumor-induced osteomalacia: Within the context of mineral metabolism research, one of the foci of investigation during the last year has been tumor-induced osteomalacia (TIO). TIO is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures and muscle weakness. It is characterized biochemically by renal phosphate wasting, hypophosphatemia, and low levels of the 1,25 (OH)2 vitamin D3. The cause is high levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor-23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very difficult to locate. We recently published a review article on the subject that represents our experience with this disease over the last ten years. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating patients. For localization, we recommend a step-wise approach utilizing functional imaging (FDG-PET and octreotide scintigraphy) followed by anatomical imaging (CT and/or MRI). If needed, selective venous sampling with measurement of FGF23 can be useful. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful;however, the medical regimen can be cumbersome and associated with complications. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed. Selective venous catheterization for the localization of phosphaturic mesenchymal tumors: As part of our investigation of TIO, we conducted a clinical study (05-D-0050) designed to determine the sensitivity, specificity and overall utility of selective venous sampling in the localization of the small mesenchymal tumors that cause tumor TIO. The primary endpoint was identification of the FGF23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and a single site (positive controls). Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 95% confidence interval (CI, 0.47-0.99) and a specificity of 0.71 (95% CI 0.29-0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection, but not in the absence of a suspicious lesion on imaging studies. In addition to the above, a report entitled Height Loss and Generalized Pain in a 35-year-old Man detailed the devastating effects of TIO,the difficulty in diagnosing the disease, and the significant challenges in localizing the offending tumor. It emphasized the utility of selective venous sampling in tumor localization and the role of measuring serum FGF23 levels not only in diagnosis, but in monitoring for cure and potential recurrence. Another focus of the Unit is the study of hypoparathyroidism as a model for understanding the role of the PTH/Gs alpha/cAMP pathway in bone and mineral metabolism. Towards this end, we participated in a meeting with an international group of experts in the area and with this group published an up-to-date review on the subject. The paper summarizes our current state of knowledge of hypoparathyroidism. It emphasizes not only what we know about the disease but also what additional knowledge is needed in order for us to understand more completely its epidemiology, etiologies and molecular pathogenesis, and clinical manifestations. In a disorder characterized by absent or inadequate parathyroid function, hypoparathyroidism presents an opportunity to appreciate the effects of absent or inadequate PTH on the skeleton and other target tissues. In an effort to discover novel ways in which to treat hypoparathyroidism, we collaborated in a proof of principal gene transfer study in rats. Gene transfer to salivary glands leads to safe and abundant secretion of therapeutic protein into either saliva or the bloodstream. We previously reported the successful transduction of rat submandibular glands with an adenoviral vector encoding human parathyroid hormone (Ad.hPTH), but unfortunately most of the hPTH was secreted into saliva. Because submandibular and parotid glands are morphologically and functionally different, we hypothesized that hPTH sorting might be different in parotid glands. After 2 days, the pattern of hPTH secretion from transduced parotid glands of intact rats was reversed from that of transduced submandibular glands, that is, most transgenic hPTH was detected in serum (5 x 1010) viral particles per gland;the saliva-to-serum ratio of total hPTH secreted was 0.04). Vector copies were localized to the targeted parotid glands, with none detected in liver or spleen. Ad.hPTH next was administered to parotid glands of parathyroidectomized rats. Two days after delivery no hPTH was detectable in saliva, but high levels were found in serum, leading to normalization of serum calcium and a significant increase in the urinary phosphorus-to-creatinine ratio. This study demonstrates for the first time differential sorting of transgenic hPTH between submandibular and parotid glands, suggesting that hPTH may be a valuable model protein for understanding the molecular basis of transgenic secretory protein sorting in these exocrine glands. This study also demonstrates the potential clinical utility of salivary gland hPTH gene therapy for patients with hypoparathyroidism. An area of investigation central to bone and mineral metabolism is tissue mineralization and ossification. In fact, one of the most debilitating aspects of the disease of FGF23 deficiency, familial tumoral calcinosis (FTC), is massive soft tissue calcification and ossification. To better understand the complicated processes involved in mineralization and the generation of the potent inhibitor of mineralization, pyrophosphate, we reviewed the subject in an invited editorial. Pyrophosphate generation is an important process that is involved in both physiologic mineralization, as takes place in hard tissues such as bone, as well as for pathologic mineralization that can take place in common and rare diseases such as atherosclerosis and FTC. Due to the fact FTC is a disease caused by absence of FGF23 and our group's interest in the role of FGF23 in mineral metabolism, this subject is of particular interest to us. Understanding the underlying mechanisms of the processes involved the pathologic calcification that takes place in FTC is certain to shed light on the processes involved in more common disorders of ectopic calcification as well as physiologic calcification. This editorial outlines our current understanding of the mineralization/mineralization inhibition process and points to new areas of investigation.